Total Synthesis of Anticancer Natural Products Using Oxidative Dearomatization

氧化脱芳构全合成抗癌天然产物

• 批准号: 9171740
• 负责人: Yu Yuan
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171740
• 关键词: Academic Research Enhancement Awards; Alkaloids; Ally; Antineoplastic Agents; Basic Science; Biological; Biology; Cancer Patient; Carbon; Cause of Death; Cells; Cephalotaxus; Cessation of life; Chemicals; Complex; Data; Development; Dose; Drug Industry; Economic Burden; Electron Transport; Electrons; Elements; Exhibits; Family; Intercept; Investigation; Laboratories; Longevity; Lymphoma; Malignant Neoplasms; Medical; Methodology; Methods; Mus; Natural Products; Navelbine ditartrate; Nerve Growth Factors; Norditerpenoids; Octanes; Organic Synthesis; Outcome; Oxidants; Paclitaxel; Patients; Phenols; Positioning Attribute; Protocols documentation; Radiation therapy; Reaction; Reagent; Regimen; Reporting; Research; Science; Scientist; Skeleton; Societies; Solid Neoplasm; Structure; Structure-Activity Relationship; System; Testing; Therapeutic Agents; United States; United States Food and Drug Administration; Up-Regulation; Vasodilation; alkaloid skeleton; analog; anticancer activity; base; chemotherapy; cycloaddition; cytotoxicity; diene; experience; improved; member; neoplastic cell; novel; novel therapeutics; operation; outcome forecast; oxidation; scaffold; skills; stereochemistry

PROJECT SUMMARY Cancer is the second leading cause of deaths in the United States and it has become a serious economic burden to society. Among the most successful treatments, natural product inspired chemotherapies such as Paclitaxel, Navelbine and Eribulin have significantly extended the life span of millions of cancer patients. It has been reported that more than 75% of the new chemical entities submitted to the Food and Drug Administration as anticancer agents between 1940 and 2010 have natural product origins. We propose to develop a novel oxidative dearomatization methodology to access the core structures of biologically active natural products and investigate its application to the total synthesis of daphmanidin A, an alkaloid showing significant cytotoxicity against murine lymphoma cells. Because some subtypes of lymphoma do not form solid tumors, their treatments commonly involve intense radiotherapy and chemotherapy. To improve the prognosis of patients who show low tolerance to current high dose regimens, new therapeutic agents with better efficacy are urgently needed. Given the cytotoxicity profiles of Daphniphyllum alkaloids, it is important to study the biology of daphmanidin A and explore its potential to become a therapeutic agent. Our preliminary data have shown that an enantioselective Michael addition / oxidative dearomatization cascade can be achieved by a one-pot operation, and the desired products are obtained with excellent stereoselectivity and yields, highlighting the remarkable efficiency of our strategy for the synthesis of these natural products. When para substituted phenols are subjected to the dearomatization, the core structures of Cephalotaxus norditerpenes are conveniently produced. When ortho substituted phenols are intercepted during the dearomatization, the spiro intermediates can serve as dienes in the subsequent [4+2] cycloaddition, resulting in the daphmanidin A type alkaloid skeletons. In the proposed research we will 1) identify the suitable single electron transfer reagent and base to enable the dearomatization for sensitive substrates under homogenous conditions; 2) study the regioselectivity for asymmetrically substituted aromatics; 3) examine the conditions to intercept spiro diene in the dearomatization; 4) elucidate the stereochemistry determining elements that control the chirality of the quaternary carbon center, and 5) apply the novel methodology to the synthesis of daphmanidin A and its pharmaceutically relevant analogues.

项目总结 癌症是美国第二大死亡原因，而且已经成为一种严重的 给社会带来经济负担。在最成功的治疗中，天然产品受到启发 紫杉醇、长春瑞滨和埃布林等化疗药物显著延长了人肺癌的寿命。 数百万癌症患者。据报道，超过75%的新化学实体 在1940年至2010年期间作为抗癌剂提交给食品和药物管理局 天然的产品来源。我们建议开发一种新的氧化脱芳构化方法来获得 生物活性天然产物的核心结构及其在全合成中的应用 瑞香素A的合成，一种对小鼠淋巴瘤细胞有显著细胞毒性的生物碱。 因为一些亚型的淋巴瘤不会形成实体瘤，他们的治疗通常包括 高强度的放射治疗和化疗。改善低耐受性患者的预后 对于目前的大剂量化疗方案，迫切需要新的疗效更好的治疗药物。vt.给出 瑞香生物碱的细胞毒性研究对瑞香素A的生物学研究具有重要意义 并探索其成为治疗剂的潜力。 我们的初步数据表明，对映体选择性的Michael加成/氧化脱芳构化 可以通过一锅操作实现级联，并以极佳的性能获得所需的产品 立体选择性和产率，突出了我们的合成策略的显著效率 这些天然产品。当对位取代苯酚进行脱芳构化时， 三尖杉酯类化合物的结构可方便地制备。当邻位取代苯酚 在脱芳构化过程中被截留，螺环中间体可以作为二烯在脱芳构化过程中使用 随后进行[4+2]环加成反应，得到瑞香素A型生物碱骨架。在建议的 研究我们将1)确定合适的单电子转移试剂和碱，以使 均相条件下敏感底物的脱芳构化；2)研究区域选择性 3)考察不对称取代芳烃中螺二烯的截留条件 4)阐明了控制手性的立体化学决定因素。 5)将新方法学应用于瑞香素A及其衍生物的合成。 与药物相关的类似物。